Problem: Congenital heart defects often require surgical repair with cardiopulmonary bypass (CPB). Unfortunately CPB causes systemic derangements that can lead to organ injury or death. Markers of injury risk and interventions to improve outcomes from CPB related-injury are limited. Alkaline phosphatase (AP) may protect against CPB injury through multiple mechanisms. AP activity, however, falls substantially following infant CPB and low post-operative AP activity is independently associated with increased post-operative support requirements. Additional research is needed to understand the role of AP during infant CPB, its use as a marker of post-operative risk, and its potential value as a therapeutic agent. This K23 project combines the study of low AP activity after infant CPB with career development aims for Dr. Davidson, ultimately preparing Dr. Davidson for future independent research in AP therapy aimed at improving outcomes after infant CPB. Overall Hypothesis: Low AP activity after infant CPB increases the risk of inflammation, organ injury, and cardiac arrest, mechanical circulatory support, or death, in part due to a decreased ability to convert harmful extracellular adenine nucleotides to adenosine in the setting of CPB induced ischemia-reperfusion injury. Proposal: Observational cohort study of 120 infants d120 days of age undergoing CPB with measurement of total and isoform specific AP activity before, during, and after CPB. Primary outcome: risk of cardiac arrest, mechanical circulatory support, or death in infants with AP activity d80 U/L versus >80 U/L. Secondary outcomes: post-operative support requirements, biomarkers of organ injury/inflammation. Pre and post-CPB serum samples will be analyzed for their ability to convert adenosine monophosphate to adenosine.
Specific Aims of the Proposed Research Project: 1) Clinical: Demonstrate a higher risk of death, cardiac arrest, or mechanical circulatory support, endotoxemia, and inflammation/organ injury in post-CPB infants with low AP activity. 2) Kinetics: Measure AP isoform-specific activity loss, recovery, and mechanism following CPB. 3) Mechanism: Determine the differential capacity of AP in pre and post-CPB serum to convert adenosine monophosphate to adenosine and demonstrate the ability to rescue this function with exogenous AP.
Specific Aims of the Career Development Plan: 1) Clinical Research Aim: Improve clinical research skills to make the transition to independent research. 2) Translational Research Aim: Improve skills in basic/translational study design, techniques, and analysis. 3) Scholarly Aim: Completion of the Masters of Clinical Science program and initiation of the Ph.D. program. Potential Impact: The results of this study will fully establish AP as a novel predictive biomarker in this population, improve the understanding of the physiologic role of AP after infant CPB, and help direct future studies of AP treatment aimed at improving outcomes after pediatric cardiac surgery.

Public Health Relevance

Alkaline phosphatase is a protein that may protect babies against injury from heart surgery, but activity of this protein decreases after surgery and very low activity may allow greater injury to the patient. This study will clarify the clinical risk of ow alkaline phosphatase activity after heart surgery in babies, as well as working to identify the reason why low alkaline phosphatase activity is potentially harmful for these children. Results could be used to guide future studies of alkaline phosphatase replacement aimed at improving outcomes for babies requiring surgery for heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL123634-04
Application #
9320760
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Scott, Jane
Project Start
2014-07-21
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Davidson, Jesse A; Urban, Tracy T; Tong, Suhong et al. (2018) Alkaline Phosphatase Activity and Endotoxemia after Infant Cardiothoracic Surgery. Shock :
Persson, Jessica N; Baird, Christine H; Tong, Suhong et al. (2018) Infant cardiopulmonary bypass: CD73 kinetics, association with clinical outcomes, and influence on serum adenosine production capacity. Pediatr Res 83:858-865
McIntosh, Amanda M; Tong, Suhong; Deakyne, Sara J et al. (2017) Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis. Pediatr Crit Care Med 18:750-757
Davidson, Jesse A; Urban, Tracy T; Baird, Christine et al. (2017) Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events. J Pediatr 190:49-55.e2
Frank, Benjamin Steven; Urban, Tracy T; Tong, Suhong et al. (2017) Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair. World J Cardiol 9:822-829
McIntosh, Amanda M; Davidson, Jesse A; Scott, Halden F (2017) The authors reply. Pediatr Crit Care Med 18:1003-1005
Davidson, Jesse A; Urban, Tracy; Tong, Suhong et al. (2016) Alkaline Phosphatase, Soluble Extracellular Adenine Nucleotides, and Adenosine Production after Infant Cardiopulmonary Bypass. PLoS One 11:e0158981
Frank, Benjamin; Davidson, Jesse; Tong, Suhong et al. (2016) Myocardial Strain and Strain Rate in Kawasaki Disease: Range, Recovery, and Relationship to Systemic Inflammation/Coronary Artery Dilation. J Clin Exp Cardiolog 7: